Medicament for the treatment of viral skin and tumour diseases

ABSTRACT

The invention relates to a medicament containing a compound of general formula (I), where R 1 =independently, a straight or branched, saturated, singly- or multiply-unsaturated, optionally substituted C 11 -C 21  alkyl, alkylene or alkinyl group, preferably a C 11 -C 15  alkyl, alkylene or alkinyl group, particularly a C 11 -C 13  alkyl, alkylene or alkinyl group, most preferably a C 13  alkyl group, R 2 =independently, a straight or branched C 1 -C 8  alkyl, alkylene or alkinyl group, preferably a C 1 -C 6  alkyl, alkylene or alkinyl group, in particular a C 2 -C 4  alkyl, alkylene or alkinyl group, most preferably a C 3  alkyl group, a —[CH 2 —(CH 2 )m-O] n H group with n=1 to 10, preferably n=1 to 5, to m=1 to 5, preferably m=1 to 3, a —CH 2 —[CH—(OH)] p  [CH 2 —R 3 ]— group, where R 3 =independently H or OH, p=1 to 7, preferably p=1 to 4, a pentose group or a hexose group, as therapeutically active agent, alone or in combination with one or several further pharmaceutical agents as a combination preparation for the treatment of viral skin diseases and/or tumor diseases, in particular caused by human papilloma virus (HPV) and/or herpes viruses and a topically acting medicament formulation and the use thereof.

The present invention relates to a pharmaceutical which comprises acompound of the formula

where R₁, independent of each other, is an unbranched or branched,saturated, singly or multiply unsaturated, optionally substitutedC₁₁-C₂₁ alkyl, alkylene or alkynyl radical, preferably a C₁₁-C₁₅ alkyl,alkylene or alkynyl radical, in particular a C₁₁-C₁₃ alkyl, alkylene oralkynyl radical, especially a C₁₃-alkyl radical, and

R₂ is, independent of each other, an unbranched or branched C₁-C₈ alkyl,alkylene or alkynyl radical, preferably a C₁-C₆ alkyl, alkylene oralkynyl radical, in particular a C₂-C₄ alkyl, alkylene or alkynylradical, especially a C₃-alkyl radical, a —[CH₂—(CH₂)_(m)—O]n-H radicalwhere n=1 to 10, preferably n=1 to 5, m=1 to 5, preferably m=1 to 3,

a —CH₂—[CH—(OH)]_(p)—(CH₂—(R₃)] radical, where R₃ is, independent ofeach other, a hydrogen or a hydroxyl radical, p=1 to 7, preferably p=1to 4, a pentose radical or a hexose radical,

as a therapeutically active compound, either alone or together with oneor more additional pharmaceutical active compounds as a combinationpreparation, for treating viral skin diseases and/or tumor diseaseswhich are caused, in particular, by human papilloma viruses (HPV) and/orherpes viruses, and also to a topically acting pharmaceuticalformulation and its use.

Papilloma viruses (HPV) are DNA viruses which infect the epithelialcells of mammals and thereby induce uncontrolled cell growth. There area very wide variety of papilloma viruses, which infect humans anddifferent animal species. In this connection, all the viral types infectthe basal epithelial cells and remain as episomes or integrate their DNAinto the host genome.

It has been known for a long time that papilloma viruses cause genitalwarts (Condyloma acuminata), ordinary and plantar warts, bowenoidpapulosis in men and women, and cervical intraepithelial neoplasias inwomen.

Depending on the method used, the detection rate for HPV is almost 100%.It is in the main HPV 6 and HPV 11 viruses which are found in warts andgenital warts (Condyloma acuminata). Since HPV 16 and HPV 18 areprincipally observed in malignant, desquamative cell carcinomas, as inthe case of cancer of the penis and of the uterine cervix, it isgenerally accepted that HPV 16 and HPV 18 are linked to malignant HPVdiseases.

At present, physical methods are predominantly used for treating genitalwarts caused by human papilloma viruses. These methods include surgicalremoval, electrocauterization, cryosurgery and laser therapy to mentionbut a few. An additional medicinal treatment is the use of Podophyllin,5-Fluorouracil, Bleomycin, Interferon, Imiquimod, etc.

Surgical treatment suffers from the disadvantage that it is veryunpleasant for the patient and can lead to further infection. Up untilnow, a topical use has involved the risk of side effects since theactive compounds employed possess cytotoxic properties or augment thecellular immune defense and can consequently induce local inflammations.This demonstrates that the therapeutic possibilities which have thus farbeen available are still not satisfactory.

In addition to this, there is the fact that the proportion ofrecurrences is very high in the case of warts and genital warts andcomplete healing can only be achieved by means of constant andconsistent treatment. For this reason, there is a need for a morereliable and comfortable treatment.

Particularly when treating genital warts, but also in connection withall the other diseases which are caused by the papilloma virus, there isa requirement for a treatment which is easy for the patient to use. Forexample, a treatment which the patient himself can use at the affectedsites and which gives good results in relatively short time, andexhibits only few or no side effects, would be suitable.

Herpes simplex viruses (HSV) are DNA viruses from the alpha subfamilyHerpetoviridae. They are divided into two groups, i.e. HSV 1, termed theoral strain, and HSV 2, termed the genital strain. Herpes simplexviruses penetrate, as a nucleocapsid, into the nerve endings and, usingthe axonal flow, reach the appurtenant ganglia. They are transmitted bysmear and droplet infection from herpes lesions or by healthy chroniccarriers. Following a primary infection, the viruses can be reactivatedonce again, symptomatically or asymptomatically, by irritation, forexample due to fever, trauma or radiation, of latently infected neurons.This reactivation depends, in particular, on the defensive condition ofthe body taken as a whole. Herpes simplex viruses can transform cellsneoplastically in animals and in cell cultures. The possibility of aninteraction between type 2 herpes simplex viruses and the genesis ofcervical carcinomas involving type 16 and type 18 human papillomaviruses is presently being discussed.

EP 0 087 161 discloses treating herpes infections by treating them witha mixture consisting of isopropyl myristate and small quantities of4-{lower alkyl}-2,6-(bis-tert-butyl)phenol containing2,6-(bis-tert-butyl)-4-hydroxytoluene or 4-(loweralkyl)-2,6-(bis-tert-butyl)phenol.

EP 0 842 660 describes a pharmaceutical composition for treating genitalwarts which are caused by human papilloma viruses. The composition whichis described comprises catechols from tea extracts (Camellia sinensis),predominantly (−)-epigallocatechol-gallate in the form of an ointment ora suppository.

An object of the present invention is therefore to find additionaleffective antiviral substances and formulations which are suitable fortreating viral skin diseases and/or tumor diseases which are caused bypapilloma viruses and/or herpes viruses.

It has now been found, surprisingly, that a pharmaceutical whichcomprises a compound according to the invention of the formula (I) asthe pharmaceutically active compound is suitable for treating viral skindiseases and/or tumor diseases.

The present invention consequently relates to a pharmaceutical whichcomprises a compound of the formula (I) as the pharmaceutically activecompound,

A-B   (I)

where A is a radical of the formula (II)

and B is a radical of the formula (III)

—O—R₂   (III),

and

R₁ is, independent of each other, an unbranched or branched, saturated,singly or multiply unsaturated, optionally substituted C₁₁-C₂₁ alkyl,alkylene or alkynyl radical, preferably a C₁₁-C₁₅ alkyl, alkylene oralkynyl radical, in particular a C₁₁-C₁₃ alkyl, alkylene or alkynylradical, especially a C₁₃-alkyl radical, and

R₂ is, independent of each other, an unbranched or branched C₁-C₈ alkylalkylene or alkynyl radical, preferably a C₁-C₆ alkyl, alkylene oralkynyl radical, in particular a C₂-C₄ alkyl, alkylene or alkynylradical, especially a C₃ alkyl radical, a —[CH₂—(CH₂)_(m)—O]_(n)—Hradical where n=1 to 10, preferably n=1 to 5, m=1 to 5, preferably m=1to 3,

a —CH₂—[CH—(OH)]_(p)—(CH₂—(R₃)] radical, where R₃ is, independent ofeach other, a hydrogen or a hydroxyl radical, p=1 to 7, preferably p=1to 4, a pentose radical or a hexose radical.

In this connection, the radical R₁ and/or the radical R₂ can,independent of each other, be substituted by a halogen, preferablyfluorine and/or chlorine, or an unbranched or branched C₁-C₆ alkyl,alkylene or alkynyl radical, preferably a C₁-C₃ alkyl, alkylene oralkynyl radical, in particular a methyl radical.

In this connection, the radical A of the compound (I) can, for example,be derived from hexanoic acid (caproic acid), heptanoic acid, octanoicacid (caprylic acid), nonanoic acid, decanoic acid (capric acid),undecanoic acid, dodecanoic acid (lauric acid), tridecanoic acid,tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoicacid (palmitic acid), heptadecanoic acid, octadecanoic acid (stearicacid), nonadecanoic acid, eicosanoic acid, heneicosanoic acid, oleicacid, linoleic acid, linolenic acid and/or arachidonic acid, preferablyfrom caproic acid, caprylic acid, capric acid, lauric acid, myristicacid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenicacid and/or arachidonic acid, particularly preferably from myristicacid.

The radical B of the compound (I) can, for example, be derived from anunbranched or branched C₁-C₈ alkyl alcohol, in particular ethanol,propanol, isopropanol, n-butanol, tert-butanol, particularly preferablyisopropanol, ethylene glycol, polyethylene glycol, propylene glycol,polypropylene glycol, glycerol, polyglycerol, a pentose sugar, such asarabitol, adonitol and xylitol, or a hexose sugar, such as sorbitol,mannitol or dulcitol, preferably from ethanol, propanol, isopropanol,butanol, ethylene glycol, polyethylene glycol, propylene glycol,polypropylene glycol, glycerol, polyglycerol, arabitol, adonitol,xylitol, sorbitol, mannitol and/or dulcitol.

The compound (I) is preferably isopropyl laureate, isopropyl myristate,isopropyl palmitate, isopropyl stearate, ethyl myristate, propylmyristate, butyl myristate and/or ethyl oleate, in particular isopropylmyristate.

In another preferred embodiment, the compound (I) is a hydrophobiccompound. According to the present invention, a hydrophobic compound isunderstood as being a compound whose solubility in water is at mostapprox. 0.2 mg/ml, in particular at most approx. 0.1 mg/ml.

The pharmaceutical comprises, for example, at least approx. 5%-75%(w/w), preferably at least approx. 10%-60% (w/w), in particular at leastapprox. 25%-55% (w/w), and especially at least approx. 35%-50% (w/w) ofthe compound of the formula (I).

In this connection, the pharmaceutical according to the invention canalso contain one or more additional pharmaceutical active compounds as acombination preparation for use which is simultaneous, separate orstaggered in time. In this context, preference is given to employing, asadditional pharmaceutical active compounds, those compounds which can beused for treating viral skin diseases and/or tumor diseases, such aspodophyllin, 5-fluorouracil, bleomycin, interferon or imiquimod, and/ormixtures which comprise at least one catechol.

In a preferred embodiment, the additional pharmaceutical active compoundis an amphiphilic or amphipathic active compound. An amphiphilic oramphipathic active compound is understood as being an active compoundwhich is composed of two functional moieties, in particular onehydrophilic moiety and one lipophilic moiety. This property might, inparticular, be able to facilitate the passage of the substance throughthe skin and achieve an improved effect. In this connection, theimproved effect may be attributable, for example, to a longer dwell timeat the desired site or to a reduction in the dose of the activecompound.

In a further preferred embodiment, the additional pharmaceutical activecompound comprises at least one catechol of the formula (IV)

in which

R₃ is —H or —OH, and

R₄ is —H or a group of the formula (V)

The catechols which are added in this connection may be obtained eithersynthetically or from natural sources. The natural sources which mayespecially be mentioned are tea plants. In this context, the naturalconstituents may be present in differing concentrations depending on thespecies and variety. In this connection, the catechols which areemployed are preferably isolated from Camellia sinensis, Camelliaasamica, Camellia bohea, Camellia chinensis or Camellia oleosa. All thecomponents of tea plants, in particular the leaves, can be used forisolating the catechols. The catechols which are employed are preferablyisolated from a tea extract.

The catechols which are employed in the present invention are preferablyepicatechol, epicatechol gallate, epigallocatechol, epigallocatecholgallate, gallocatechol and gallocatechol gallate, in particular(−)-epicatechol, (−)-epicatechol gallate, (−)-epigallocatechol,(−)-epigallocatechol gallate, (+)-gallocatechol and (−)-gallocatecholgallate.

The catechols can be used both individually and in the form of mixtureshaving different compositions. A catechol mixture contains approx. 2-20%(w/w), preferably approx. 4-15% (w/w), in particular approx. 10-11%(w/w) of (−)-epicatechol, approx. 2-20% (w/w), preferably approx. 5-15%(w/w), in particular approx. 5-7% (w/w) of (−)-epicatechol gallate,approx. 1-25% (w/w), preferably approx. 3-15% (w/w), in particularapprox. 5-7% (w/w) of (−)-epigallocatechol, approx. 40-75% (w/w),preferably approx. 57-67% (w/w), in particular approx. 61-66% (w/w) of(−)-epigallocatechol gallate, approx. 0.05-5% (w/w), preferably approx.0.1-1% (w/w), in particular approx. 0.1-0.6% (w/w) of (+)-gallocatecholand/or approx. 0.5-20% (w/w), preferably approx. 1-10% (w/w), inparticular approx. 1-5% (w/w) of (−)-gallocatechol gallate.

In a preferred embodiment, the catechol mixture is composed of approx.5.9% (w/w) of (−)-epicatechol, approx. 12.6% (w/w) of (−)-epicatecholgallate, approx. 17.6% (w/w) of (−)-epigallocatechol, approx. 53.9%(w/w) of (−)-epigallocatechol gallate and/or approx. 1.4% (w/w) of(−)-gallocatechol. A composition of this nature is known under the namePolyphenon® 100.

In a particularly preferred embodiment, the catechol mixture is composedof approx. 10.8% (w/w) of (−)-epicatechol, approx. 6.5% (w/w) of(−)-epicatechol gallate, approx. 9.2% (w/w) of (−)-epigallocatechol,approx. 54.8% (w/w) of (−)-epigallocatechol gallate and/or approx. 4.0%(w/w) of (−)-gallocatechol gallate. A composition of this nature isknown under the name Polyphenon® E.

The pharmaceutical according to the invention comprises, for example,approx. 1-30% (w/w), preferably approx. 2-20% (w/w) and, in particular,approx. 15-18% (w/w) of a catechol and at least approx. 5-90% (w/w),preferably at least approx. 10-70% (w/w), in particular at least approx.25-60% (w/w) and, especially, at least approx. 35-50% (w/w) of thecompound (I).

The familiar methods of pharmaceutical technology are used, in acustomary manner, for preparing pharmaceuticals which comprise one ormore compounds according to the invention and/or for using thesepharmaceuticals in the application according to the invention. For this,the active compounds are worked up, together with suitable,pharmaceutically acceptable auxiliary substances and carrier substances,into the medicinal forms which are suitable for the differentindications and sites of administration. In this context, thepharmaceuticals can be prepared such that the rate of release in eachcase desired, for example a rapid accumulation and/or a delayed-releaseor depot effect, is achieved.

Customary emulsions, gels, ointments, creams of the mixed-phase oramphiphilic emulsion systems (oil/water-water/oil mixed phase), and alsoliposomes and transfersomes or plasters, preferably ointments andcreams, particularly preferably an ointment, may be mentioned forconventional application to the skin or mucosa. The active compound ispreferably applied locally in the region in which there is a skin ormucosal change and/or disease.

In addition to the known uses on the skin and/or mucosa, the followingare suitable for use as special pharmaceutical preparations which can beadministered topically, locally or regionally: emulsions, creams,ointments, effervescent tablets or suppositories which can beadministered genitally, vaginally or rectally, in particular genitallyand vaginally. Rectal capsules can also be prepared on the basis ofgelatin or other carrier substances. Suitable suppository bases arehardened fats, such as Witepsol®, Massa Estarium®, Novata®, coconutbutter, glycerol/gelatin pastes, glycerol/soap gels and polyethyleneglycols.

Examples of suitable auxiliary and/or carrier substances are sodiumalginate, as a gelatinizing agent for preparing a suitable base, orcellulose derivatives, such as guar or xanthan gum, inorganicgelatinizing agents, such as aluminum hydroxide or bentonites (what aretermed thixotropic gel-formers), polyacrylic acid derivatives, such asCarbopol®, polyvinylpyrrolidone, microcrystalline cellulose andcarboxymethylcellulose. Amphiphilic low molecular weight and highermolecular weight compounds, and also phospholipids, are also suitable.The gels can be present either as water-based hydrogels or ashydrophobic organogels, for example based on mixtures of low and highmolecular weight paraffin hydrocarbons and vaseline. The hydrophilicorganogels can be prepared, for example, on the basis of high molecularweight polyethylene glycols. These gelatinous forms are washable.However, the organogels which are preferred are the hydrophobicorganogels. Particular preference is given to hydrophobic auxiliarysubstances and additives, such as petroleum jelly, wax, oleyl alcohol,propylene glycol monostearate and propylene glycol monopalmitostearate.It is, of course, likewise possible to add skin-sedating and/orinflammation-inhibiting additives which are known to the skilled person,such as synthetically prepared active compounds and/or extracts and/oractive compounds from medicinal plants, in particular bisobolol andpanthenol. It is furthermore also possible to add dyes, for exampleyellow and/or red iron oxide and/or titanium dioxide for the purpose ofmatching as regards color.

Emulsifiers which can be employed are anionic, cationic or neutralsurfactants, for example alkali metal soaps, metal soaps, amine soaps,sulfonated compounds, invert soaps, higher fatty alcohols, partial fattyacid esters of sorbitan and polyoxyethylene sorbitan, e.g. lanettetypes, wool wax, lanolin or other synthetic products for preparing theoil/water and/or water/oil emulsions.

It is possible to use vaseline, natural or synthetic waxes, fatty acids,fatty alcohols, fatty acid esters, for example as monoglycerides,diglycerides or triglycerides, paraffin oil or vegetable oils,hydrogenated castor oil or coconut oil, hog fat, synthetic fats, forexample based on, caprylic acid, capric acid, lauric acid or stearicacid, such as Softisan®, or triglyceride mixtures, such as Miglyol®, canbe used as lipids, in the form of fatty and/or oleaginous and/or waxycomponents for preparing the ointments, creams or emulsions.

It is possible to use, for example, osmotically active acids andalkaline solutions, for example hydrochloric acid, citric acid, sodiumhydroxide solution, potassium hydroxide solution, sodium hydrogencarbonate, and, in addition, buffer systems, such as citrate, phosphate,tris buffer or triethanolamine, for adjusting the pH. It is possible toadd preservatives as well, such as methyl benzoate or propyl benzoate(parabens) or sorbic acid, for increasing the stability.

Pastes, powders and solutions may be mentioned as additional forms whichcan be applied topically. As consistency-imparting bases, the pastesfrequently contain hydrophobic and hydrophilic auxiliary substances,preferably, however, hydrophobic auxiliary substances containing a veryhigh proportion of solids. In order to increase dispersity, and alsoflowability and slipperiness, and also to prevent agglomerates, thepowders or topically applicable powders can, for example, contain starchspecies, such as wheat or rice starch, flame-dispersed silicon dioxideor siliceous earth, which also serve as diluent.

The medicinal forms which are in each case suitable can be produced onthe basis of pharmaceutico-physical principles in conformity withformulation guidelines and methods known to a skilled person.

The pharmaceutical according, to the invention preferably comprisesapprox. 35% (w/w) of isopropyl myristate, approx. 15% (w/w) of at leastone catechol, approx. 24.5% (w/w) of petroleum jelly, approx. 20% (w/w)of wax, approx. 5% (w/w) of propylene glycol monostearate or propyleneglycol monopalmitostearate and approx. 0.5% (w/w) of oleyl alcohol.

The pharmaceutical of the present invention and/or of a pharmaceuticalmetabolites is used in the treatment of viral skin diseases and/ortumour diseases.

The term pharmaceutical metabolite is to be understood as meaning one ormore compounds which arise during use as a result of biologicalmetabolism. These metabolites can be intermediates arising duringintermediary metabolism or the end products of metabolism. Themetabolites are preferably metabolic products which arise as a result ofapplication to the skin and/or mucosa, in particular hydrolysis productsof the compound having the formula (I). Conceivable hydrolysis productscan be derived, for example, from radical A and/or radical B.

Viral skin diseases are understood as being skin diseases which areinduced or caused by viruses and/or associated with viral infections.They include, for example, skin diseases such as warts, genital warts,benign tumors of the skin and/or mucosa which are caused by papillomaviruses, for example verrucae plantares, verrucae vulgares, verrucaeplanae juveniles, epidermodysplasia verruciformis, Condylomataacuminata, Condylomata plana, bowenoid papulosis, papillomas on thelarynx and oral mucosa, focal epithelial hyperplasia, herpes labialis,Kaposi's sarcoma, varicella and shingles.

These viral skin diseases and/or tumor diseases are caused by at leastone papilloma virus or viruses, in particular human papilloma viruses,such as HPV 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18,19-29, 31, 32, 34, 36-38, 46-50, 56, 58, by at least one herpes virus orherpes viruses, such as herpes simplex virus 1, herpes simplex virus 2,varicella zoster virus or human herpes virus, such as 1, 2, 3, 4, 7 or8.

The figures and the following examples are intended to clarify theinvention without restricting it. Skilled persons can modify theinvention appropriately, within the bounds of customary ability, withoutdeparting from the protective scope.

EXAMPLES

Clinical Study for Comparing an Ointment and a Cream ContainingIsopropyl Myristate

93 patients (in each case divided equally into men and women) took partin a multicenter clinical study which was carried out at a total of 30different centers in Germany and Russia. The study was randomized andperformed double-blind. The study examined the clinical efficacy of twodifferent formulations of isopropyl myristate (an ointment and a cream)in the treatment of external genital warts.

The formulations which were tested had the following compositions:

Cream 1:

Substance Quantity (in % w/w) Cera alba 6.996 Monomuls 2.798 LameformTGI 5.598 Cetiol V 6.996 Isopropyl myristate 13.992 Tocopherol 0.699Controx KS 0.066 Glycerol 6.996 Disodium EDTA 0.001 Magnesium sulfate1.399 D-Panthenol 0.699 Purified water 53.678 Red Iron Oxide* 0.025Yellow Iron Oxide* 0.054 *The dyes were added for matching as regardscolor.

Ointment 1:

Substance Quantity (in % w/w) White Petrolatum, USP 34.023 White Wax, NF25.000 Isopropyl Myristate, NF 35.000 Oleyl Alcohol, NF 0.500 PropyleneGlycol 5.000 Monostearate, NF Red Iron Oxide* 0.022 Yellow Iron Oxide*0.055 Titanium Dioxide, USP* 0.400 *The dyes were added for matching asregards color.

The patients applied the topical study medication three times daily oruntil the genital warts had completely healed or for a maximum of twelveweeks.

The following data were collected during the study:

Complete Healing (in %)

Cream 1 Ointment 1 Male 39.1 42.1 Female 35.0 33.3

Partial healing (in %); this corresponds to at least 75% healing basedon the total area of the genital warts.

Cream 1 Ointment 1 Male 43.5 63.2 Female 50.0 52.4

The results of the study show that a surprisingly high degree ofcomplete healing, or partial healing, takes place as compared with theplacebo values from similar studies using different formulations, inassociation with which the spontaneous regression of genital warts isapprox. 20% in the case of women and approx. 5% in the case of men(Aldara™ (Imiquimod) Cream, 5% Product Monograph, marketed by 3MPharmaceuticals, Northridge, Calif., Beutner K R et al. (1998) J Am AcadDermatol 38, 230-9, Edwards L et al. (1998) Arch Dermatol 134 (1);25-30).

This therapeutic effect is attributed to the isopropyl myristate, anantiviral effect of which has consequently been demonstrated for thefirst time.

Clinical Study for Comparing an Ointment and a Cream ContainingIsopropyl Myristate and Polyphenon® E

272 patients (equally divided between men and women in each case) tookpart in a multicenter clinical study which was carried out at a total of30 different centers in Germany and Russia. The study was randomized andperformed double-blind. The study examined the clinical efficacy of twodifferent formulations of isopropyl myristate and Polyphenon® E (anointment and a cream), as against the formulations from Example 1containing isopropyl myristate, in the treatment of external genitalwarts.

The Polyphenon® E-containing formulations which were tested had thefollowing compositions:

Cream 2:

Substance Quantity (in % w/w) Polyphenon ® E 10.000 Cera alba 5.263Monomuls 2.105 Lameform TGI 4.211 Cetiol V 5.263 Isopropyl myristate10.526 Tocopherol 0.526 Controx KS 0.050 Glycerol 5.263 Disodium EDTA0.001 Magnesium sulfate 1.053 D-Panthenol 0.526 Purified water 55.213

Ointment 2:

Substance Quantity (in % w/w) Polyphenon ® E 15.000 White Petrolatum,USP 24.500 White Wax, NF 20.000 Isopropyl Myristate, NF 35.000 OleylAlcohol, NF 0.500 Propylene Glycol 5.000 Monostearate, NF

The patients applied the topical study medication three times daily oruntil the genital warts had completely healed or for a maximum of twelveweeks.

During the study, the following data were collected:

Complete Healing (in %)

Cream 1 Cream 2 Ointment 1 Ointment 2 Male 39.1 53.9 42.1 61.0 Female35.0 39.5 33.3 56.8

Partial Healing (≥75% in %)

Cream 1 Cream 2 Ointment 1 Ointment 2 Male 43.5 64.2 63.2 80.5 Female50.0 47.4 52.4 81.1

Analysis of the study shows that, when comparing ointment 1 and cream 1,on the one hand, and ointment 2 and cream 2, on the other hand, thecombination of isopropyl myristate and Polyphenon® E leads to asurprising increase in the efficacy of the pharmaceutical.

If the efficacy of ointment 2 is now compared with that of cream 2, itthen becomes evident that ointment 2 is markedly more effective thancream 2. This suggests a synergistic effect between the Polyphenon® Eand the isopropyl myristate in the hydrophobic ointment.

As a result of this synergistic effect, the individual active compoundsin the formulation can, in order to achieve the same effect, be employedin substantially smaller quantities than the corresponding individualcomponents. Consequently, the use of this synergistic formulation hasadvantages not only with regard to the effect but also with regard tothe cost of preparing this formulation, something which in turn can havea positive effect on the cost of treating the patient.

1. A pharmaceutical composition comprising: (i) a compound having theformulaA-B  (I), wherein A is a radical having the formula

and wherein B is a radical having the formula—O—R₂  (III), and wherein R₁ is, independent of each other, anunbranched or branched, saturated, singly or multiply unsaturated,optionally substituted C₁₃-C₂₁ alkyl, alkylene, or alkynyl radical, andR₂ is, independent of each other, an unbranched or branched C₁-C₈ alkyl,alkylene, or alkynyl radical; and (ii) a mixture of catechols comprising4-15% (w/w) of (−)-epicatechol, 2-20% (w/w) of (−)-epicatechol gallate,3-15% (w/w) of (−)-epigallocatechol, 40-75% (w/w) of(−)-epigallocatechol gallate, 0.1-1% (w/w) of (+)-gallocatechol, and1-10% (w/w) of (−)-gallocatechol gallate; and wherein the pharmaceuticalcomprises at least 5-50% (w/w) of the compound of formula (I).
 2. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition comprises 1-30% (w/w) of said mixture of catechols and atleast 10-50% (w/w) of said compound of formula (I).
 3. Thepharmaceutical composition of claim 2, wherein said pharmaceuticalcomposition comprises 2-20% (w/w) of said mixture of catechols.
 4. Thepharmaceutical composition of claim 3, wherein said pharmaceuticalcomposition comprises 15-18% (w/w) of said mixture of catechols.
 5. Thepharmaceutical composition of claim 2, wherein said pharmaceuticalcomposition comprises at least 25-50% (w/w) of said compound of formula(I).
 6. The pharmaceutical composition of claim 5, wherein saidpharmaceutical composition comprises at least 35-50% (w/w) of saidcompound of formula (I).
 7. The pharmaceutical composition of claim 1,wherein said mixture of catechols comprises 5-7% (w/w) of said(−)-epicatechol gallate.
 8. The pharmaceutical composition of claim 1,wherein said mixture of catechols comprises 0.1-0.6% (w/w) of said(+)-gallocatechol.
 9. The pharmaceutical composition of claim 1, whereinsaid mixture of catechols comprises 1-5% (w/w) of said (−)-gallocatecholgallate.
 10. The pharmaceutical composition of claim 1, wherein saidmixture of catechols comprises 10.8% (w/w) of (−)-epicatechol, 6.5%(w/w) of (−)-epicatechol gallate, 9.2% (w/w) of (−)-epigallocatechol,54.8% (w/w) of (−)-epigallocatechol gallate, and/or 4.0% (w/w) of(−)-gallocatechol gallate.
 11. The pharmaceutical composition of claim1, wherein said pharmaceutical composition comprises at least 10-50%(w/w) of said compound of formula (I).
 12. The pharmaceuticalcomposition of claim 11, wherein said pharmaceutical compositioncomprises at least 25-50% (w/w) of said compound of formula (I).
 13. Thepharmaceutical composition of claim 12, wherein said pharmaceuticalcomposition comprises at least 35-50% (w/w) of said compound of formula(I).
 14. The pharmaceutical composition of claim 1, wherein saidcatechols are isolated from a tea extract.
 15. The pharmaceuticalcomposition of claim 1, wherein one or more additional pharmaceuticalcompound(s) is/are administered simultaneously or separately.
 16. Thepharmaceutical composition of claim 15, wherein said one or moreadditional pharmaceutical compound(s) is/are amphiphilic.
 17. Thepharmaceutical composition of claim 1, further comprising additivesand/or auxiliary substances.
 18. The pharmaceutical composition of claim17, wherein said additives and/or auxiliary substances are hydrophobicand are selected from the group consisting of petroleum jelly, wax,oleyl alcohol, propylene glycol monostearate, and propylene glycolmonopalmitostearate.
 19. A pharmaceutical composition comprising 35%(w/w) of a compound having the formulaA-B  (I), wherein A is a radical having the formula

and wherein B is a radical having the formula—O—R₂  (III), and wherein R₁ is, independent of each other, anunbranched or branched, saturated, singly or multiply unsaturated,optionally substituted C₁₃-C₂₁ alkyl, alkylene, or alkynyl radical, andR₂ is, independent of each other, an unbranched or branched C₁-C₈ alkyl,alkylene, or alkynyl radical; and wherein said pharmaceuticalcomposition further comprises 15% (w/w) of a mixture of catecholscomprising 4-15% (w/w) of (−)-epicatechol, 2-20% (w/w) of(−)-epicatechol gallate, 3-15% (w/w) of (−)-epigallocatechol, 40-75%(w/w) of (−)-epigallocatechol gallate, 0.1-1% (w/w) of(+)-gallocatechol, 1-10% (w/w) of (−)-gallocatechol gallate, 24.5% (w/w)of petroleum jelly, 20% (w/w) of wax, 5% (w/w) of propylene glycolmonostearate or propylene glycol monopalmitostearate, and 0.5% (w/w) ofoleyl alcohol.
 20. A method of treating a papilloma virus-induced skindisease or benign tumor disease in a patient, said method comprisingadministering to a patient a pharmaceutical composition of claim
 1. 21.The method of claim 20, wherein said papilloma virus-induced skindisease or benign tumor disease is caused by HPV 1, 2, 3, 4, 5, 6, 8, 9,11, 12, 13, 14, 15, 16, 17, 18, 19-29, 31, 32, 34, 36-38, 46-50, 56, or58.
 22. The method of claim 20, wherein said papilloma virus-inducedskin diseases are warts or genital warts and the papilloma virus-inducedbenign tumors are of the skin and/or mucosa.
 23. The method of claim 22,wherein said papilloma virus-induced benign tumors of the skin and/ormucosa are verrucae plantares, verrucae vulgares, verrucae planaejuveniles, epidermodysplasia verruciformis, Condylomata acuminata,Condylomata plana, bowenoid papulosis, papillomas on the larynx and oralmucosa, or focal epithelial hyperplasia.
 24. The method of claim 20,wherein said pharmaceutical composition is applied topically.
 25. Themethod of claim 24, wherein said pharmaceutical composition is appliedgenitally or vaginally.